Prognostic factors for survival after salvage total laryngectomy following radiotherapy or chemoradiation failure: a 10-year retrospective longitudinal study in eastern Denmark.

OBJECTIVE: The primary aims were to determine the rates of and prognostic factors for overall survival, disease-specific survival and disease-free survival following salvage total laryngectomy. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 142 patients in eastern Denmark undergoing salvage total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. MAIN OUTCOME MEASURES: 5-year overall survival, 5-year disease-specific survival, 5-year disease-free survival and prognostic factors for these outcomes. RESULTS: 5-year overall survival, disease-specific survival and disease-free survival were 37.7%, 54.9% and 55.3%, respectively. N classification at primary diagnosis, lymph node excision and postoperative complications within 1 year after salvage total laryngectomy were prognostic factors for shorter overall survival, disease-specific survival and disease-free survival. Residual tumour/recurrence was negatively associated with overall survival, close or involved resection margins with disease-specific survival, and second primary cancer was associated with longer disease-specific survival and disease-free survival. Nine per cent of all patients had residual tumour and 33.8% developed a recurrence. CONCLUSION: Our overall survival, disease-specific survival and disease-free survival findings are in accordance with previous studies. With the purpose of identifying recurrent tumour, we suggest extra attention being given to patients with higher N classification and need for lymph node excision during salvage total laryngectomy along with use of frozen sections. The high number of patients with recurrence within 1 year after salvage total laryngectomy occurred although thorough and regular follow-up visits were performed.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Risk factors for postoperative complications after total laryngectomy following radiotherapy or chemoradiation: a 10-year retrospective longitudinal study in Eastern Denmark.

OBJECTIVES: To determine the rates of and risk factors for postoperative complications following total laryngectomy in patients treated with radiotherapy or chemoradiation. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 143 patients undergoing total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. MAIN OUTCOME MEASURES: Overall postoperative complications and fistula formation. RESULTS: Overall postoperative complications, fistula formation, wound infection, bleeding and wound necrosis within one year after total laryngectomy occurred in 56.6%, 42.3%, 31.0%, 11.3% and 9.2% of patients, respectively. Stenosis of the pharynx/oesophagus and stoma shrinkage within five years after surgery were each seen in 18.2% of cases. In 66.7% of cases, conservative treatment of the fistulas was chosen. Rehospitalisations within five years occurred for 44.8% with a median rate of 1.5 (range 1-11). Smoking status (P = 0.005 and 0.013) and chronic obstructive pulmonary disease (COPD) (P = 0.013 and 0.011) were significant risk factors for both overall postoperative complications and fistula formation in uni- and multivariate analysis. Tumour localisation in the hypopharynx was associated with overall postoperative complications (P = 0.036). Residual tumour or cancer recurrence was associated with late-onset fistulas (P < 0.001). CONCLUSION: The frequencies of postoperative complications after total laryngectomy were comparable with similar international studies, although fistula formation rate is increasing in Denmark. We suggest optimising treatment of COPD and to further encourage to smoking cessation. We propose that development of fistulas >2 months after surgery prompts immediate biopsies. Additionally, we suggest standardised registration of surgical techniques to identify variables affecting the frequency of postoperative complications.

Nasopharyngeal secretory immunoglobulins in children with recurrent acute otitis media and secretory otitis media.

Secretory IgA (SIgA) and secretory IgM (SIgM), total IgA and total IgM were measured in plasma and nasopharyngeal secretions (NPS) from young children with different degrees of otitis proneness. Significantly higher levels of plasma IgM and lower levels of NPS-SIgM were found in children with recurrent episodes of acute otitis media (rAOM) compared with children suffering from secretory otitis media (SOM) and healthy controls. Both plasma IgA and NPS-SIgA were evenly distributed in the three groups of children investigated, and in most children the levels of NPS-SIgA exceeded plasma IgA levels. Plasma SIgA was significantly increased in children with rAOM and SOM, probably resulting from frequent occurrence of inflammatory events at the nasopharyngeal level. No correlation could be demonstrated between NPS-SIgA and plasma IgA, or between NPS-SIgM and plasma IgM. Also, for both NPS-SIgA and NPS-SIgM, there was no correlation with age. A negative correlation was observed between the transudation index of albumin to the nasopharynx and the ratio of NPS-SIgA to total NPS-IgA. A ratio of 1 (100%) corresponded to a transudation index of 8%. The ratios of NPS-SIgA to total NPS-IgA varied considerably and a range of 39%-88% could only to some extent be explained by transudation of plasma IgA to NPS. The results of the present study show that the children with rAOM and SOM are well furnished with locally produced SIgA antibodies at the nasopharyngeal level. In children with SOM, the nasopharyngeal hypofunction in the case of low NPS-SIgM seems to be less pronounced compared with that of otitis-prone children.

Plasma IgG, IgG subclasses and acute-phase proteins in children with recurrent acute otitis media.

Quantitation of IgG, IgG subclasses and acute-phase proteins was performed in plasma samples from 156 children, aged 2 to 162 months, with varying degrees of otitis proneness. None of the children had acute otitis media or had received any antibiotics 3 weeks before the examination. Children with recurrent acute otitis media (rAOM) had significantly higher levels of total IgG, IgG1, and significantly lower levels of IgG2 than healthy children (p less than 0.02, p less than 0.0003, and p less than 0.03, respectively). However, the low levels of IgG2 found in the rAOM children could at least, to some extent, be explained by the observation that these children were somewhat younger than the healthy children. Except for recurrent episodes of common colds, children suffering from secretory otitis media (SOM) most often show no clinical signs of inflammatory events. Nevertheless, children with SOM had raised levels of plasma IgG1, indicating recurrent polyclonal stimulation of the immune apparatus, which seems to be less pronounced than that of rAOM children. Levels of acute-phase proteins, haptoglobin, orosomucoid and alpha 1-antitrypsin were evenly distributed in the children investigated, reflecting that they had no acute illness at the time of plasma sampling.

Association between keratin staining patterns and the structural and functional aspects of palatine tonsil epithelium.

The keratin composition of stratified squamous epithelia has a complex pattern, which varies in different regions and as a result of pathological developments. The exact factors responsible for the characteristic keratin composition in a given epithelium are unknown. However, the environment, including factors from the connective tissue, is known to influence epithelial morphology and keratin composition. We here report that the reticulated squamous epithelium of the crypts of palatine tonsils shows an extensive staining for keratins 5 and 19 in basal as well as suprabasal cells, in contrast to neighbouring non-reticulated crypt epithelium and the epithelium at the tonsillar surface, in which staining is restricted to basal cells. The reticulation of the crypt epithelium is thought to be initiated by infiltration of immune-related cells in a preexistent non-reticulated epithelium. The extensive staining for keratins 5 and 19 in reticulated crypt epithelium correlates with the presence of numerous immune system-related cells and marked expression of intercellular adhesion molecule-1 (ICAM-1), thought to be involved in inflammatory and immunological responses. The results suggest that the massive lymphocytic traffic in the reticulated crypt epithelium and the overall distinct immune environment are responsible for the unique keratin staining pattern observed.

Mucosal immunity to Pseudomonas aeruginosa alginate in cystic fibrosis.

Patients with cystic fibrosis commonly acquire chronic pulmonary infection with alginate-producing Pseudomonas aeruginosa. The infection remains localized at the mucosal surfaces of the airways. Using enzyme-linked immunosorbent assays immunoglobulin concentrations and titers of specific antibodies to purified P. aeruginosa alginate and to P. aeruginosa sonicated antigens were measured in tears, saliva, sputum and serum. CF patients had significantly higher concentrations of IgG, IgA and SIgA in serum and saliva than controls. They also had significantly higher levels of specific antibodies to alginate and sonicated antigen in secretions and serum. Local production of IgA, IgG and IgM antibodies to P. aeruginosa was demonstrated. Only a minor proportion of specific IgA antibodies were present as secretory IgA in tears, saliva and sputum. The ratio of alginate-specific SIgA to specific monomeric IgA in sputum was significantly lower than the similar ratio in saliva, whereas the same ratio for specific P. aeruginosa sonicate antigens was found in saliva and sputum.

Quantitative aspects of IgD and secretory immunoglobulins in middle ear effusions.

Levels of the true secretory immunoglobulins, secretory IgA (SIgA) and secretory IgM (SIgM) were determined in middle ear effusions (MEEs) from children with secretory otitis media (SOM) and correlated to the MEE levels of IgD. Double sandwich enzyme-linked immunosorbent assays (ELISA) were used for the quantitative determinations. The levels of SIgM were expressed arbitrarily in units using a nasopharyngeal secretion pool as a standard. The quantitative data substantiated a local synthesis of IgD to the middle ear cavity. In 8/45 MEEs more than 600 mg/l of IgD could be calculated and between 70% and 98% could be considered to be locally produced. A statistically significant correlation was observed between SIgA and SIgM. The results are discussed in the context of the possibility that IgD plasma cells located in the middle ear cavity may primarily originate from the nasopharyngeal tonsils.

The post-winter prevalence rate of middle ear effusion in four-year-old children, judged by tympanometry.

Tympanometry and otologic examinations were performed in 373 four-year-old children randomly selected from the Central National Register at the end of February, 1979. A close interaural correlation of the middle ear pressures of a child was found and therefore the tympanometric results represent related as well as independent data. Consequently, the post-winter prevalence rates of type B tympanograms were calculated according to different sampling units: per all ears 13.7%; per right ears 12.9%; per left ears 14.5%; per ears selected at random 13.9%. Additionally, the prevalence rate was estimated per child at 20.4% type B in at least one ear and at 7% type B in both ears. Based upon the literature the validity of the tympanometric method in detecting middle ear effusion is described. The predictive values of positive and negative tests mostly depend on the degree of the cutoff point (pass--fail point) which has been chosen. In this study the cutoff point was the presence of a type B tympanogram. The advantage and disadvantage of applying 'one ear' or 'one child' as the sampling unit is discussed from a statistical as well as a clinical point of view. When calculating either per ear or per child no sex differences in the prevalence rates could be proved.

Influence of antibiotic treatment on the isolation rate of group A streptococci from peritonsillar abscesses.

In a prospective one-year study, group A streptococci were cultured from pus specimens from 13 of 71 patients (18%) with peritonsillar abscesses. The isolation rate was significantly lower (7/57 = 12%) in patients who had received antibiotic treatment before specimen collection than in patients who had not received such treatment (6/12 = 50%). Group A streptococcus antigen detection tests on pus, using a commercially available diagnostic kit, had a low sensitivity (5/13 = 38%). It was concluded that in patients treated with antibiotics prior to collection of specimens, the absence of group A streptococcus on culture does not rule out that this organism could have been the principal etiologic agent.

Nasopharyngeal bacteriology and secretory otitis media in young children.

A prevalence study was performed on the nasopharyngeal bacteriology of 112 young children, aged 4-6 years. During the preceding 2 years, 74 of these children had suffered from secretory otitis media (SOM) and 40 had had normal middle ear ventilation. At the examination, one-third of the children with SOM had improved their middle ear status (previous SOM group), whereas otomicroscopy and tympanometry remained unchanged in the healthy group. The nasopharyngeal swab sample was obtained from behind the soft palate by the oral route. The isolation rate of Streptococcus pneumoniae was significantly higher in the SOM group than in the two other groups of children (p less than 0.006). The most commonly isolated capsular types of pneumococci were 6, 19, and 23, corresponding to the types involved in acute otitis media. The isolation rate of Haemophilus influenzae was 50% and an even distribution was found among the three groups of children examined. Biotypes I, II, III and IV accounted for 75% of the isolated cases of H. influenzae. As in acute otitis media, S. pneumoniae also seemed to play an important role in the pathogenesis of tubal dysfunction and SOM, and the difference is probably caused by variations in the quantitative colonization of pneumococci in the nasopharynx.

Experimental studies of cholesteatomas. In vivo studies on epithelial-mesenchymal interaction and bone resorption in the immunodeficient "nude" mouse.

A model for studying different aspects of human cholesteatomas in vivo and in the immunodeficient "nude" mouse is described. Epithelial-mesenchymal interaction was studied in human cholesteatoma membranes, transplanted to the flank region. Findings of cystic lesions lined by stratified keratinizing epithelium were frequent, and the connective tissue reaction was weak. Furthermore, human cholesteatoma membranes were transplanted into the middle ear cavity of 'nude' mice. After 21-28 days, bone resorption was found in the labyrinthine capsule, but not always with signs of inflammation.

Ribotyping of strains of Moraxella (Branhamella) catarrhalis cultured from the nasopharynx and middle ear of children with otitis media.

Moraxella (Branhaomella) catarrhalis is frequently present in the nasopharyngeal microflora of small children, especially during episodes of acute otitis media . By means of ribotyping (restriction endonuclease analysis of chromosomal DNA combined with rRNA probing), we studied the genetic heterogeneity of 78 cultures of M. catarrhalis obtained from different localities in the nasopharynx of nine young children with secretory otitis media. Using HindIII and PstI as endonucleases, five different ribotypes were recognized, representing at least five different genotypes of M. catarrhalis. The distribution of these types was found to be almost identical to the distribution among 16 M. catarrhalis strains cultured from middle ear exudates of 16 children with acute otitis media. Ribotype HAPA was found in two-thirds of all the cultures investigated, and 44% of the children harboured more than one ribotype in the nasopharynx at the same time. The vast majority of the nasopharyngeal M. catarrhalis cultures were beta-lactamase positive. One child had both a HAPA ribotype, beta-lactamase-negative strain in the nasopharyngeal secretions, and HAPA ribotype, beta-lactamase-positive strains at the entrance of the eustachian tube, the nasopharyngeal tonsils, the folds of the nasopharyngeal tonsils and the oropharynx. All except one of the M. catarrhalis strains cultured from middle ear exudates were beta-lactamase positive.

Mucosal immunity and bacteriology of the eustachian tube.

The pathogenesis of otitis media is a multifaceted process that is not completely understood. Eustachian tube dysfunction plays a central but uncertain role, as do viral and bacterial microorganisms. Of the latter, the three most important are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. This article reviews the various mechanisms of infection and the immune system's response to them.

Secretory IgA enzyme immunoassay. Application of a model for computation of the standard curve.

An enzyme-linked immunosorbent assay (ELISA) is applied for quantitation of secretory IgA (SIgA) in nasopharyngeal secretions (NPS) and saliva. In principle, both the alpha and secretory component determinants of SIgA are utilized in a two-site sandwich technique. Dilutions of a SIgA solution prepared from colostrum (Col-SIgA) are used for standards. A continuous SIgA standard curve, describing the relationship between the absorbance of the coloured end product and the corresponding Col-SIgA dilution, is computed by means of a fitting procedure based on a model. The variation (SD) of the absorbance was found to be proportional to the absorbance level. Knowing the SD of the absorbance, the total variation of the SIgA estimates could be calculated experimentally by means of Monte Carlo methods. Based on these results, the analytical range was chosen from 2000 micrograms/l to 50 micrograms/l of SIgA. Inhibition experiments revealed that plasma IgA could be added to the NPS in equal amounts to the SIgA content without it interfering with the SIgA measurements. Percentage recovery (median) of known amounts of SIgA added to NPS was 96%. In NPS from children suffering from recurrent upper respiratory tract infections the median SIgA level was 1.44 g/l (interquartile range 0.61-2.43 g/l); in saliva from healthy children the median SIgA content was 77 mg/l (interquartile range 56-182 mg/l).

IgD in nasopharyngeal secretions and tonsils from otitis-prone children.

Quantification of IgD was performed by ELISA in 180 plasma samples and 83 nasopharyngeal secretions (NPS) from children aged 2-162 months with varying degrees of recurrent otitis media. Furthermore, in 24 of the children the density of the IgD-immunocytes (IgD-cells) was calculated in immunoenzyme-stained cross-sections of their nasopharyngeal tonsils (NPT). Owing to a considerable variation of the IgD cell density throughout the NPT, a semi-quantitative counting system was applied. An irregular distribution of plasma IgD was observed during childhood and maximum levels were found between 48 and 72 months of age. However, an even distribution of plasma IgD was found among the four groups of children investigated. Based on calculations of the transudation of albumin from plasma to the NPS the amount of locally produced IgD in NPS (NPS-IgD (local] was estimated to 88% (range 41-99%). Significantly higher levels of NPS-IgD (local) were found in otitis-prone children than in the other groups. Moreover, a positive correlation was calculated between levels of NPS-IgD (local) and NPT-IgD cell density, indicating that NPT, being the local lymphoepithelial tissue, also functions as an important source of NPS-IgD. NPS-IgD was not found to be associated with secretory component, indicating a passive transfer of IgD through the mucosal membranes. Our results support the hypothesis of an association between the occurrence of IgD in the mucosa and secretions of the upper respiratory tract with localized inflammatory events.